Is GBE1 p.Lys57Arg (c.170A>G) pathogenic?

GBE1 p.Lys57Arg (c.170A>G) is classified Conflicting classifications of pathogenicity in GBE1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0717); Rare (popmax 0.131%, sas); Associated with Glycogen storage disease IV, classic hepatic.

What condition is associated with GBE1 p.Lys57Arg (c.170A>G)?

GBE1 p.Lys57Arg (c.170A>G) is associated with Glycogen storage disease IV, classic hepatic, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

How common is GBE1 p.Lys57Arg (c.170A>G) in the general population?

GBE1 p.Lys57Arg (c.170A>G) is rare (popmax 0.131%, sas) (gnomAD).

What do computational predictors say about GBE1 p.Lys57Arg (c.170A>G)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

GBE1 p.Lys57Arg

c.170A>G · rs544821452 · VCV195023

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glycogen storage disease IV, classic hepatic

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -4
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	0.114	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% South Asian · 110/84,248 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.00708% 111/1,567,864 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.131%	766
Remaining individualsnot grpmax-eligible	0.00165%	60,748

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GBE1
Protein: p.Lys57Arg
Coding: c.170A>G
MANE Select: NM_000158
dbSNP: rs544821452
Type: single nucleotide variant
Location: chr3:81705587 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB
Residue 57: an α-helix

Full GBE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glycogen storage disease IV, classic hepatic — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease due to glycogen branching enzyme deficiency

Similar variants

GBE1 p.Lys57Ter Pathogenic ★ same residue
GBE1 p.Lys57Glu Uncertain significance ★ ⚠ same residue
GBE1 c.1109-1G>T Likely pathogenic ★★ same condition
GBE1 c.1236+1G>A Likely pathogenic ★★ same condition
GBE1 c.1336-1G>A Pathogenic/Likely pathogenic ★★ same condition
GBE1 c.143+1G>A Pathogenic ★★ same condition
GBE1 c.143+2T>C Pathogenic/Likely pathogenic ★★ same condition
GBE1 c.144-1G>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gbe1-p-lys57arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown